Despite the existence of many useful antibiotics, bacterial, parasitic, and viral infections remain a major problem affecting human and animal health, agriculture, and industrial processes. The continued emergence of resistant bacteria and viruses heightens the need for the identification of new and effective agents for the inhibition of these pathogens. The most advantageous antiviral and antibacterial agents are those which can be used to selectively control pathogens without posing any health hazards for humans or animals. The identification of such agents is fraught with difficulties and uncertainties due to the biochemical complexities of viral and bacterial pathogens as well as the ability of these organisms to develop resistance. The identification of antiviral and antibacterial agents remains an empirical process requiring extensive effort and the investment of substantial resources.
A particularly serious pathogen to humans is the influenza virus. Influenza virus epidemics occur every winter, causing significant morbidity and mortality in the U.S. population. The disease has a high infection rate and annual costs to the U.S. are estimated to exceed one billion dollars. The elderly are at high risk for serious complications from influenza, and excess mortality in the U.S. is estimated to be 10,000-20,000 each year. Currently available vaccines and drugs have failed to effectively control influenza in humans. Furthermore, vaccines must be reformulated each year in response to antigenic variation and are frequently ineffective against new influenza variants. A need exists for new, broad-spectrum anti-influenza drugs that act by different mechanisms.
Influenza viruses are enveloped RNA viruses that are classified into three serological types: A, B, and C. The two major surface glycoproteins of influenza viruses are hemagglutinin (HA) and neuraminidase (NA). These glycoproteins are essential for infectivity and offer potential targets for antiviral drug development. HA is responsible for viral attachment to host cells by binding to terminal sialic acid residues on host cell surface glycoconjugates, and HA is also involved in mediating membrane fusion. NA (also called sialidase or acy-ineuraminylhydrolase) destroys the host cell viral receptor by catalyzing the hydrolysis of .alpha.-2,6-glycosidic bonds to terminal sialic acid residues of surface glycoconjugates. This facilitates release and prevents aggregation of progeny virus. Influenza NA, which accounts for 5-10% of the virus protein, has an approximate molecular weight (MW) of 250,000 and lies mostly outside of the viral membrane.
Sialic acids (N-acetyl neuraminic acid, referred to herein as NeuAc) are nine carbon ketoses which have the unusual feature of a highly acidic carboxyl group (pK.sub.a .about.2.8) immediately adjacent to the anomeric carbon. Sialic acids are typically found in terminal glycosidic linkages of cell surface glycoproteins and glycolipids. A variety of biological phenomena are associated with recognition of sialosides, including viral replication, escape of immune detection, and cell adhesion (Schauer, R. Trends Biochem. Sci. 1985, 10, 357-360; Biology of the Sialic Acids ed. A. Rosenberg, Plenum Press, New York, 1995) providing considerable interest in the development of inhibitors of sialyltransferases and sialidases for mechanistic and clinical applications (Taylor, G. Curr. Opin. Struc. Biol. 1996, 6, 830-837; Colman, P. M., Pure Appl. Chem. 1995, 67, 1683-1688; Bamford, M. J. J Enz. Inhib. 1995, 10, 1-16; Khan, S. H. & Matta, K. L. In Glycoconjugates, Composition, Structure, and Function. pp361-378. ed., Allen, H. J. & Kisailus, E. C. Marcel Dekker, Inc. New York, 1992).
A number of compounds have been evaluated as in vitro inhibitors of influenza neuraminidase, and among the most potent thus far described is 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). A DANA analog, 2-deoxy-2,3-dehydro-N-(trifluoroacetyl) neuraminic acid (FANA), exhibited greater in vitro activity (Palese, P., R. W. Compans [1976]J. Gen. Virology 33:159-163). Several new DANA analogs have been described that possess in vivo antiviral effects (Von Itzstein, LM et al. [1991] WO 91/16320; O'Neill, G. [1993]J. NIH Res. 5:40-42).
The observation that DANA was an effective in vitro inhibitor of NA has resulted in the preparation of a large number of synthetic derivatives varied mainly at the 2-, 4-, 5-, and 6-positions (for example, Meindl, P., G. Bodo, P. Palese, J. Schulman, H. Tuppy [1974] Virology 58:457-463; Schreiner, E., E. Zbiral, R. G. Kleineidam, R. Schauer [1991] Liebigs Ann. Chem. 129-134; Kumar, W., S. Tanenbaum, M. Brashner [1982] Carbohyd. Res. 103:281-285; Vasella, A., R. Wyler [1991] Helv. Chim. Acta 74:451-463). Numerous synthetic sialic acid (NANA) analogs (for example, Glanzer, B. I., Z. Gyorgydeak, B. Bernet, A. Vasella [1991] Helv. Chim. Acta 74:343-368; Yamamoto, Y., H. Kumazawa, K. Inami, T. Teshimi, T. Shiba [1992] Tet. Lett. 33:5791-5794; Mack, H., R. Brossmer [1992] Tet. Lett. 33:1867-1870) have also been reported. A few NA inhibitors that are not pyrans or furans have been described, including isoquinolines(Brammer, K. W., C. R. McDonald, M. S. Tute [1968] Nature 219:515-517), .alpha.-mercaptocinnamic acids and imidazoles (Haskell, T. H., F. E. Peterson, D. Watson, N. R. Plessas, T. Culbertson [1970] J. Med. Chem. 13:697-704), oxamic acids (Brossmer, R., G. Keilich, D. Zeigler [1977] Hoppe-Seyler 's Z. Physiol. Chem. 358:391-396), the piperidine, siastatin B, and derivatives(Kudo, T., Y. Nishimura, S. Kondo, T. Takeuchi [1993] J. Antibiot. 46:300-309), and plant flavonoids (Nagal, T., Y. Miyaichi, T. Tomimori, Y. Suzuki, H. Yamada [1992] Antiviral Res. 19:207-217). One attempt at rational design of inhibitors has resulted in a class of compounds based on 2-deoxy-2,3-didehydro-D-N-acetylneuraminic acid (Neu5Ac2en) (Brammer et al., supra).
There remains a need to identify effective compounds which can combat bacterial, parasitic, and viral infections. The ability to use such compounds for other applications such as to modulate immune responses, regulate inflammation, and/or inhibit metastasis would additionally be advantageous.